Gastrointestinal Stromal Tumors: A Retrospective Study at a Tertiary Care Center in Saudi Arabia in the Last Decade

Introduction: Gastrointestinal stromal tumors (GISTs) are a significant subset of mesenchymal tumors primarily found in the gastrointestinal tract, impacting diagnostic and therapeutic approaches. Understanding their epidemiology is crucial for improving patient care and advancing treatment strategies. Methodology: Our study at a Saudi tertiary hospital analyzed 50 patients with GIST, focusing on demographics, tumor locations, and risk assessments. We examined predictors of tumor size, including mitosis frequency, and assessed the impact of anatomical location and risk on clinical outcomes using RStudio software (Posit, Boston, MA). Results: Among 50 patients with GIST, 36 (72.0%) were male with a median age of 60.5 years, and most tumors (33, 66.0%) were in the stomach. Risk assessments categorized tumors as follows: 20 (40.0%) low risk, 12 (24.0%) high risk, 7 (14.0%) moderate risk, 7 (14.0%) very low risk, and 4 (8.0%) no risk. Most tumors were low-grade (41, 82.0%) and nonmetastatic (47, 94.0%), predominantly spindle cell type (37, 74.0%). Tumor size varied significantly across risk categories: high-risk tumors averaged 10.3 cm versus 0.5 cm for no risk and 3.5 cm for very low risk (P < 0.001). Mitosis frequency differed significantly by risk category and tumor grade (P < 0.001). Tumor grade varied notably with risk categories and morphologic types, especially high-grade tumors in high-risk groups (8, 66.7%) and epithelioid tumors (2, 100%). Multivariable analysis identified predictors of tumor size: anatomical location (extra-GI, intra-abdominal; beta = 7.08, P = 0.011) and risk assessment (low risk, beta = 6.91, P = 0.001; moderate risk, beta = 11.2, P < 0.001; high risk, beta = 8.93, P < 0.001). Liver metastasis did not differ significantly across gender, anatomical location, risk assessment, or tumor grade. Conclusions: In Saudi Arabia, GISTs predominantly affect males and are primarily located in the stomach. Our findings highlight significant variations in tumor size and grade based on risk assessments and anatomical location. Most GISTs were low-grade, nonmetastatic, and spindle cell type, emphasizing the need for enhanced research to improve diagnostics, tailor treatments, and optimize outcomes in the region.


Introduction
Gastrointestinal stromal tumors (GISTs) are the predominant type of mesenchymal tumors in the GI tract.They constitute 80% of all such tumors and represent a small fraction, between 0.1% and 3%, of all GI cancers [1,2].Around 30% of GISTs are cancerous [3].GISTs can form throughout the entire gastrointestinal tract, but they are primarily found in the stomach (60%) and the small intestine (20% to 30%) [4][5][6].GISTs can occasionally develop outside the GI tract, often in areas like the omentum, mesentery, or retroperitoneum.Initially categorized as smooth muscle tumors in the 1980s, advances in immunohistochemistry and the identification of gain-of-function mutations over the past two decades have established GISTs as distinct entities [7].
GISTs mostly have well-defined boundaries and commonly develop within the muscularis propria layer of the gastrointestinal tract.Their size can vary, with high-risk GISTs having a median tumor size of about 8.9 cm.[8,9].The majority of GISTs typically display intense and widespread staining in the cytoplasm for KIT, while a smaller number may show a staining pattern characterized by dots or a membranous distribution [10][11][12].The intensity and manner in which KIT is detected immunohistochemically do not influence the probability of responding to treatment [13].
Understanding the epidemiology of GIST in Saudi Arabia is crucial, especially given the minimal data available in the literature.It helps recognize patterns and prevalence, improving diagnostic practices and raising awareness among healthcare providers and patients.Specific epidemiological data can reveal variations in GIST subtypes and treatment responses, aiding in developing tailored treatment strategies and effective healthcare resource allocation.Additionally, it supports the formulation of public health policies, 1 enhances patient outcomes, and guides research efforts for new diagnostic tools and therapies.At a tertiary hospital in Saudi Arabia, our study aimed to comprehensively analyze demographic characteristics, tumor locations, risk assessments, and tumor grades among 50 patients diagnosed with GIST.We focused on understanding correlations between numerical variables and differences across categorical groups, particularly examining tumor size and mitosis frequency across varying risk assessment categories.Additionally, our research delved into identifying predictors of tumor size through rigorous univariable and multivariable regression analyses, highlighting the significance of anatomical location and risk assessment in shaping clinical outcomes for these patients.

Materials And Methods
The data were gathered from King Abdulaziz University Hospital between 2013 and 2023, encompassing all confirmed GIST cases diagnosed during this period.Ethical approval was obtained from the Research Ethics Committee of King Abdulaziz University, Faculty of Medicine (Reference No. 207-27, Unit of Biomedical Ethics).The data were extracted from medical records while maintaining patient confidentiality.We diagnose GIST patients and classify them for risk assessment based on the GEIS Guidelines [14].For extragastrointestinal GIST, classification is conducted according to the NIH criteria, as modified by the Joensuu Risk Stratification [15].

Statistical Analysis
The statistical analysis was carried out using RStudio software (R version 4.3.1).Categorical variables were described using frequencies and percentages.The Shapiro-Wilk test was used to assess the normality of numerical variables.Results showed significant p values (p = 0.022, p = 0.005 and p < 0.001 for age, tumor size and mitosis frequency, respectively).This indicated non-normally distributed variables.Numerical variables were summarized as median (interquartile range [IQR]).Statistical differences in patients' groups based on categorical variables were assessed using a Fisher's exact test.Spearman's correlation test was applied to evaluate the relationships between tumor size, age, and mitosis frequency.Differences in numerical variables across categorical groups were assessed using the Wilcoxon rank sum test or the Kruskal-Wallis rank sum test.Univariable and multivariable linear regression analyses were conducted to identify significant predictors of tumor size.The default significance level was set at p < 0.05.

Description of the characteristics and outcomes of patients
The study included 50 patients, with 36 (72.0%) males and 14 (28.0%)females.The anatomical location of the tumors was primarily in the stomach (66.0%), followed by the jejunum (14.0%).Regarding risk assessment, 40.0% of the tumors were classified as low risk, 24.0% as high risk, 14.0% as moderate risk, 14.0% as very low risk, and 8.0% had no risk.Most tumors were low grade (82.0%), with 94.0% having no metastasis.The majority of tumors were of the spindle cell type (74.0%), followed by mixed (22.0%) and epithelioid (4.0%) types (Table 1).The median age of the patients was 60.5 years (IQR, 42.0 to 69.0).The median tumor size was 6.0 cm (IQR, 3.5 to 10.0), and the median mitosis count per 50 HPF was 4.0 (IQR, 2.0 to 4.8, Table 2).The frequency distributions of numerical variables are depicted in Figure 1.

Differences in Numerical Variables Across Categorical Groups
There was a significant difference in tumor size across risk assessment categories, with medians of 0.5 cm (IQR, 0.5 to 0.5) for no risk, 3.5 cm (IQR, 2.5 to 4.5) for very low risk, 5.8 cm (IQR, 3.8 to 7.6) for low risk, 11.5 cm (IQR, 6.3 to 11.8) for moderate risk, and 10.3 cm (IQR, 7.7 to 12.1) for high risk (p < 0.001).Similarly, mitosis frequency showed significant differences across risk assessment categories (p < 0.001) and tumor grade (p < 0.001, Table 3).

Results of bivariate correlations between numerical variables
The scatterplot between tumor size and age (Figure 2A) shows a weak negative correlation, indicating no significant relationship between these variables.The scatterplot between mitosis frequency and age (Figure 2B) also shows a weak correlation, showing no significant relationship.In contrast, the scatterplot between mitosis frequency and tumor size (Figure 2C) indicated no significant correlation.Based on risk assessment, there was a significant difference in tumor grade across different risk assessment categories (p < 0.001).High-grade tumors were more prevalent in the high-risk group (66.7%) compared to none in the no risk, very low risk, and low risk groups.All tumors in the no risk, very low risk, and low risk groups were low grade (Table 4).

Discussion
The Dutch GIST Registry cohort consisted of 1,425 patients with an almost equal sex distribution, comprising 46% female and 54% male patients [16].In contrast, our study included 50 patients with a significantly higher proportion of males, accounting for 72% of the cohort, compared to 28% of females.According to Rong et al. (2020), among patients with GIST, there is a slight predilection for men to develop the disease compared to women, with a distribution of 54% and 46%, respectively [17].
In our cohort of GIST patients, the majority of tumors were located in the stomach, accounting for 66% of cases.This distribution aligns well with existing literature, which also identifies the stomach as the most common site for GISTs [18][19][20].
The Based on these clinicopathological parameters, the NIH and NCCN have developed systems to predict GIST behavior through a risk assessment framework that categorizes tumors as very low risk, low risk, intermediate risk, or high risk [22].In our analysis of GIST risk assessment, we found that 40.0% of tumors were categorized as low risk, indicating a relatively favorable prognosis.Conversely, 24.0% were classified as high risk, suggesting a more aggressive disease course requiring intensive management.Moderate-risk tumors accounted for 14.0% of cases, while very low-risk tumors and those with no identified risk constituted 14.0% and 8.0%, respectively.In contrast, previous studies, such as those by Brabec et al. (2009) and Brady-West & Blake (2012), have predominantly reported higher proportions of tumors falling into the high-risk category [23,24].
In our cohort, a significant proportion of GIST tumors were identified as low grade, accounting for the majority at 82.0%.This finding underscores the predominantly indolent nature of these tumors within our study population.Moreover, a striking 94.0% of these cases exhibited no evidence of metastasis.These statistics highlight the generally favorable prognosis associated with low-grade GIST tumors, affirming their typically slow progression and less aggressive clinical course.Such observations underscore the importance of early detection and tailored management strategies aimed at optimizing patient outcomes in GIST management.
In our study, spindle cell tumors were the most predominant histological subtype, followed by mixed-type tumors and epithelioid tumors, respectively.This pattern contrasts with the commonly accepted classifications in the literature, where GISTs are typically categorized into three main histological subtypes: spindle cell type (most common, approximately 70%), epithelioid type (20-25%), and mixed spindle cell and epithelioid type.This deviation highlights the unique distribution observed in our cohort, with mixed-type tumors occupying the second position in prevalence [25][26][27].Our findings underscore the heterogeneity in GIST presentation and highlight the importance of risk assessment and histological subtypes in guiding personalized treatment approaches and predicting patient outcomes.
In our study of GIST patients, we identified significant variations in tumor size across different risk assessment categories based on the modified NIH consensus criteria [28].Tumors classified as no risk tended to be smaller, while those categorized as very low, low, moderate, and high risk demonstrated progressively larger median sizes.This finding highlights the clear association between risk assessment according to these criteria and tumor size within our dataset.
Additionally, we found significant differences in mitosis frequency across risk assessment categories and tumor grades.These findings highlight the histopathological diversity among GISTs and emphasize the importance of evaluating both tumor size and mitotic activity in guiding clinical management and predicting outcomes for patients with GISTs.
Our analysis revealed that gender, tumor morphological type, and anatomical location (gastrointestinal or extra-gastrointestinal) showed no significant associations with age, tumor size, or mitosis frequency.This suggests that these factors may not independently influence these key characteristics in our study cohort of GIST patients.These findings underscore the complexity of GIST pathology, where risk assessment and other clinical factors may play more crucial roles in determining disease progression and management strategies.
In our study of GISTs, bivariate correlation analyses revealed nuanced relationships among key numerical variables.The scatterplot examining tumor size against age showed a weak negative correlation, suggesting a tendency for slightly smaller tumors in older patients, although this relationship was not statistically significant.Similarly, the scatterplot of mitosis frequency against age displayed a weak correlation, indicating that age does not notably influence the rate of cell division within GISTs.Importantly, the scatterplot of mitosis frequency against tumor size revealed no significant correlation, suggesting that tumor size and mitotic activity vary independently within our study cohort.These findings underscore the complex interplay among age, tumor size, and mitotic activity in GIST pathology, emphasizing the need for comprehensive evaluation of multiple factors in understanding disease characteristics and guiding clinical management strategies.
In the context of evaluating tumor characteristics and their association with risk factors, it was observed that tumor grade distribution significantly varied among different risk assessment categories.High-grade tumors were predominantly found in patients classified under the high-risk category, while those categorized as no risk, very low risk, or low risk exclusively presented with low-grade tumors.This suggests a clear correlation between higher risk assessment and increased tumor grade.Additionally, when analyzing tumors based on morphologic types, epithelioid tumors were more frequently high-grade compared to spindle and mixed tumors, indicating a significant relationship between morphologic type and tumor grade.Despite these findings, no significant differences were detected in the occurrence of liver metastasis when considering factors such as gender, anatomical location, risk assessment category, tumor grade, or morphologic type, suggesting that these variables may not be major determinants of metastatic behavior in this context.
We found a significant correlation between tumor size and both anatomical location and risk assessment.
Specifically, tumors situated in extra-gastrointestinal intra-abdominal sites tend to manifest larger sizes, while higher risk assessments align with increased tumor dimensions.This is consistent with findings from Ghartimagar et al. (2021), where they observed that clinical presentations of GISTs are heavily influenced by tumor location and size.Mesenteric extra-gastrointestinal stromal tumors (E-GISTs), for instance, may remain asymptomatic for an extended period as they have ample space to grow before clinical symptoms become apparent [29].
In the multivariable analysis, anatomical location and risk assessment remain significant predictors of tumor size.This means that their influence on tumor size is independent of the other factors being considered.For example, even when considering other variables, tumors in extra-gastrointestinal, intraabdominal organs are typically larger, and tumors classified as moderate or high risk are larger as well.

Conclusions
Our study highlights key characteristics of GISTs within our cohort, emphasizing the predominance of male patients and gastric tumors.Our findings align with existing literature regarding the typical age range and common tumor locations for GISTs.
The majority of tumors in our cohort were low-grade and non-metastatic, indicating a generally favorable prognosis.Histological analysis revealed spindle cell tumors as the most common subtype, with a notable prevalence of mixed-type tumors, underscoring the diversity in GIST presentation.
Tumor size and mitosis frequency varied significantly across different risk categories, confirming the importance of these factors in risk stratification and prognosis.While gender, tumor morphology, and anatomical location did not show significant associations with key characteristics, the study reinforces the complexity of GIST pathology.
Our findings support the necessity of individualized treatment strategies based on comprehensive risk assessment and highlight the value of further research to refine clinical management and improve patient outcomes in Saudi Arabia.
range; SD: standard deviation are based on a Wilcoxon rank sum test or a Kruskal-Wallis rank sum test

FIGURE 2 :
FIGURE 2: Scatterplots depicting the correlations between tumor size and age (A), mitosis frequency and age (B) and mitosis frequency and tumor size (C).p values are based on Spearman's correlation tests because all the variables were non-normally distributed according to the Shpairo-Wilk test, including age (p = 0.022), mitosis frequency (p < 0.001) and tumor size (p = 0.005) median age of 60.5 years for our patients diagnosed with GISTs in our study places them within the middle-age bracket, generally considered to range from 45 to 65 years.This age statistic serves as a central indicator of the age distribution among our study population, underscoring the typical age group most frequently affected by GISTs.Supporting this observation, previous research by Farag et al. (2017) and Joensuu et al. (2013) has found that the highest incidence of GISTs occurs in individuals aged 60 to 74, with a significant number of cases also observed in those aged 75 and older.This finding is consistent with the age profile seen in our data [21].